Oral health disorders, such as gum disease and periodontitis, are widespread among modern human populations. Indeed, in the U.S. it is estimated that nearly 1 out of 2 American adults—aged 30 and older—have mild to severe periodontitis (Eke et al. (2012) J. Dent. Res. 91:914-920). The severity of such conditions increases when they are not treated and can lead not only to local oral problems, such as bone and early tooth loss, but also systemic disorders, such as heart disease.
In particular, periodontitis is a local inflammation that occurs as a result of host response against specific microorganisms and eventually leads to the tissue destruction and systemic complications. Once periodontal inflammation is initiated, the cascade of inflammatory events includes an amplified loop until the infection is contained and injury is confined (Genco (1992) J. Periodontol. 63 (4 Suppl.):338-355). The early actions of the host response are later replaced by more specific mechanisms and eventually become redundant. Thus, it is important, as in other biologic processes, to limit the response and to allow the inflammation to resolve. While it has been shown that many molecules (“on signals”) participate in the initiation and development of the host defense mechanisms, a recent paradigm in periodontal disease pathogenesis emphasizes the importance of counterregulatory molecules (“off signals”) in the resolution of inflammatory response to control its magnitude and duration (Van Dyke (2011) J. Clin. Periodontol. 38 (Suppl. 11) 119:125). Omega-3 polyunsaturated fatty acids (n-3 PUFA) are essential fatty acids provided by dietary sources and exert anti-inflammatory effects to limit the inflammatory cascade due to their hypolipidemic properties. Resolvins are derived from omega-3 fatty acids, EPA and DHA (resolvin E1 and resolvin D1 respectively). The anti-inflammatory and proresolving actions of the resolvins and protections (also derived from DHA) have already been documented in several animal models of inflammatory diseases and tissue injury including periodontal disease (Serhan et al. (2003) J. Immunol. 171:6856-6865; Hasturk et al. (2006) FASEB J. 20:401-403; Hasturk et al. (2007) J. Immunol. 179:7021-7029). In rabbit periodontitis and inflammation-induced bone destruction, one of the resolvins, i.e., resolvin E1 (RVE1) reduces inflammation protects from bone loss and stimulates tissue regeneration (Hasturk et al. (2006) FASEB J. 20:401-403; Hasturk et al. (2007) J. Immunol. 179:7021-7029).
Despite these results, however, few agonists of endogenous resolution programs, as opposed to inhibitors of the inflammatory process or immunosuppressives, are known. Rather than treating or preventing the root causes of oral conditions that would benefit from increased oral osteogenesis, current dental practices are largely limited to surgical procedures to treat the results. For example, current periodontal surgical procedures include open flap debridement, osseous surgery, and guided tissue regeneration and bone grafting. In cases of moderate to advanced periodontitis, surgical treatment, when coupled with regular post-treatment maintenance of the periodontal space, often results in little to no further breakdown of the site, and the halting of tooth loss in approximately 85% of patients (Kaldahl et al. (1996) J. Periodontol. 67:103-108). However, current procedures provide minimal tissue (e.g., bone) regeneration potential. Prevention strategies and associated therapies are generally aimed at removal of calculus and microorganisms that lead to periodontal breakdown and then maintenance of a healthy space, as opposed to rebuilding damaged and/or lost tissue. Thus, there is a great need to identify agents that can increase oral osteogenesis and methods for treating and preventing oral conditions that would benefit from increased oral osteogenesis using such agents.